It has been clearly shown that the sympathetic nervous system (SNS) can modulate immune responses. The aim of this project is to examine, at the cellular level, the nature of the interaction of the SNS with immune cells. Removal of SNS input by chemical destruction of sympathetic fibers triggers predictable changes in immune parameters. Since norepinephrine (NE) is the major neurotransmitter of the SNS, it is likely that this modulation is at least partly NE-driven. While many results are consistent with the involvement of NE, none have clearly demonstrated that it is the (or the only) transmitter involved, and some evidence points to the involvement of neuropeptide Y. The interaction of neurotransmitter with receptors on target cells is a complex process about which many questions still remain. The aim of this project is to better characterize (a) the transmitter released by the SNS, (b) the receptors on its target cells, and (c) the second messenger system(s) which is/are triggered. The project will have two compartments. The first is an in vivo approach in which time-release pellets containing various NE and neuropeptide Y agonists and antagonists are implanted into mice. The resulting changes in serum antibody titers and intracellular cytokine and cAMP levels will provide information about which ligands are involved in this interaction. Part two of the study is an in vitro approach in which the same ligands are added to splenocytes in culture in order to mimic the in vivo response. The relevance of this work is two-fold. First, elucidation of part of the complex mechanism by which nerve cells interact with immune cells will facilitate the planning of appropriate strategies for situations in which the SNS may have pathophysiological effects on immunity, such as chronic stress. Second, many norepinephrine ligands are currently used in drug therapy (i.e., beta blockers, bronchodilators), and these studies will provide insight into the potential consequences of such therapy on immunity.